Experimental Xenotransplantation in Nonhuman Primates Using Distantly Related Donor Species

Ye, Y.; Cooper, D. K. C.

doi:10.1007/978-3-642-97323-9_24

Cited by 4 publications

(1 citation statement)

References 3 publications

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“…If scientific barriers can be surmounted, xenotransplantation utilizing pigs would provide the unique opportunity to develop a safe and readily available supply of organs, allowing treatment of many of the greater than 111 000 people currently on United Network for Organ Sharing (UNOS) waitlists in the United States alone 1 . Genetic modifications have effectively reduced antibody‐, complement‐, and coagulation‐mediated mechanisms of pig organ xenograft injury 2–6 . However, these modifications fail to attenuate thrombocytopenia during the first days following transplant in pig‐to‐primate xenotransplantation models, 7–13 and platelet deposition is prominent within failing cell and organ xenografts 3,14–17 .…”

Section: Introductionmentioning

confidence: 99%

Humanized von Willebrand factor reduces platelet sequestration in ex vivo and in vivo xenotransplant models

Connolly

Kuravi²,

Burdorf

et al. 2021

Xenotransplantation

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The transplantation of organs across species offers the potential to solve the shortage of human organs. While activation of human platelets by human von Willebrand factor (vWF) requires vWF activation by shear stress, contact between human platelets and porcine vWF (pvWF) leads to spontaneous platelet adhesion and activation. This non‐physiologic interaction may contribute to the thrombocytopenia and coagulation pathway dysregulation often associated with xenotransplantation of pig organs in nonhuman primates. Pigs genetically modified to decrease antibody and complement‐dependent rejection (GTKO.hCD46) were engineered to express humanized pvWF (h*pvWF) by replacing a pvWF gene region that encodes the glycoprotein Ib‐binding site with human cDNA orthologs. This modification corrected for non‐physiologic human platelet aggregation on exposure to pig plasma, while preserving in vitro platelet activation by collagen. Organs from pigs with h*pvWF demonstrated reduced platelet sequestration during lung (p ≤ .01) and liver (p ≤ .038 within 4 h) perfusion ex vivo with human blood and after pig‐to‐baboon lung transplantation (p ≤ .007). Residual platelet sequestration and activation were not prevented by the blockade of canonical platelet adhesion pathways. The h*pvWF modification prevents physiologically inappropriate activation of human or baboon platelets by porcine vWF, addressing one cause of the thrombocytopenia and platelet activation observed with xenotransplantation.

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Section: Introductionmentioning

confidence: 99%

Humanized von Willebrand factor reduces platelet sequestration in ex vivo and in vivo xenotransplant models

Connolly

Kuravi²,

Burdorf

et al. 2021

Xenotransplantation

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Xenograft rejection: molecular mechanisms and therapeutic prospects

Azimzadeh¹,

Meyer²,

Ravanat

et al. 1996

Hematol Cell Ther

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The use of animal organs for transplantation in humans is seen as a potential solution to the short supply of human donor organs available for clinical transplantation. However, while several attempts at clinical xenografting have been made over the last ninety years, xenotransplantation has not matched the success of allotransplantation, because of a vigorous rejection response. Xenograft rejection is mediated by mechanisms that differ from those involved in alloreactivity and which are inadequately controlled by conventional immunosuppressive agents. Xenotransplantation therefore requires the development of specific strategies to overcome rejection, through modification of the host immunity or production of genetically engineered pig organs. This article reviews the cellular and molecular events underlying xenograft rejection and the potential strategies of prevention and gives a brief history of the main attempts at clinical xenotransplantation since the beginning of the century.

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The acceptability of pig organ xenografts to patients awaiting a transplant

Arundeii

1997

Xenotransplantation

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As the waiting lists for allotransplants of heart, kidney, and liver continue to grow, alternative sources of organs for transplantation are being sought: xenografts from pigs to humans could be a solution. However, is this solution acceptable to patients? To answer this question, we sought opinions, using a questionnaire, from 277 patients on a waiting list for a cadaver transplant for either a kidney (207), heart, or heart/lung transplant (70); there was a 65% (188) response rate. Approximately 75% of respondents had heard of xenografting; 50% would accept a xenograft for themselves and 43% for a relative; and 10% found a xenograft to be unacceptable and 40% were unsure and wanted more information. The most acceptable donor animal was the pig (27%), but 24% would accept organs from any animal; 68% had no objection to breeding animals as a source of organs and considered that the most appropriate use of animal tissue to be when no human organs were available. Thus, a minimum of 50% and a maximum of 90% of patients awaiting an allograft would accept a xenograft, although most would prefer a human rather than an animal donor.

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Experimental Xenotransplantation in Nonhuman Primates Using Distantly Related Donor Species

Cited by 4 publications

References 3 publications

Humanized von Willebrand factor reduces platelet sequestration in ex vivo and in vivo xenotransplant models

Humanized von Willebrand factor reduces platelet sequestration in ex vivo and in vivo xenotransplant models

Xenograft rejection: molecular mechanisms and therapeutic prospects

The acceptability of pig organ xenografts to patients awaiting a transplant

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